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Objective: The purpose of this study was to evaluate the lateral mortise approach for performing therapeutic ankle injections., Materials and Methods: Fluoroscopically guided ankle joint injections performed from November 2009 through June 2011 using the lateral ankle mortise approach were retrospectively reviewed. Data recorded included age, sex, fluoroscopic time, person performing the procedure, injection location, and preprocedure and postprocedure pain levels. Radiographs were reviewed for arthritis on a modified Kellgren-Lawrence scale, and the degree of anterior tibiotalar and lateral mortise narrowing was graded from none to severe. Univariate and multivariate statistical analyses were performed., Results: Fifty-three injections were performed on 46 patients (mean age, 50.2 years; mean fluoroscopic time, 44.3 ± 47.3 seconds). Fifty injections in 44 patients were successful with the lateral mortise approach. The degrees of arthritis and anterior tibiotalar joint narrowing were moderate in 22.6% and 20.8% of cases and severe in 39.6% and 32.1% of cases. Lateral mortise narrowing was moderate in 9.4% and severe in 1.9% of cases. Average pre-procedure and postprocedure pain levels were 5.3/10 ± 2.4/10 and 1.7/10 ± 2.3/10. Multivariate analysis showed that increased fluoroscopic time was associated with moderate to severe lateral mortise narrowing (p = 0.011) but that arthritis score (p = 0.811) and degree of anterior tibiotalar joint narrowing (p = 0.416) were not. Pain reduction was associated with a higher preinjection pain score (p ≤ 0.001)., Conclusion: The lateral mortise approach is an effective alternative to the anterior medial approach for performing therapeutic ankle injections. It is especially useful when moderate to severe ankle arthritis or anterior tibiotalar joint narrowing is present.